Platelet-activating factor (PAF) has recently been identified as an acetyl glyceryl ether phosphorylcholine (AGEPC), i.e., 1-O-hexadecyl/octadecyl-2-acetyl-sn-glyceryl-3-phosphorylcholine (Hanahan D. J. et al., J. Biol. Chem. 255:5514, 1980). Even before its chemical identification, PAF had been linked to various biological activities and pathways making it one of the important mediators responsible for a variety of physiological processes including activation or coagulation of platelets, pathogenesis of immune complex deposition, smooth muscle contraction, inflammation, hypotension, shock, pain, edema as well as respiratory, cardiovascular, renal and intravascular alterations. Since these physiological processes are in turn associated with a large group of diseases, for example, inflammatory disease, nephritis, stroke and other cardiovascular disorders, hypotension, shock, psoriasis, allergic and skin diseases, asthma, lung edema, peptic or stomach ulcer, dental pain, and adult respiratory distress syndrome, more and more scientific investigation has been focused on the search of a PAF antagonist or inhibitor for treating or preventing these common diseases.
The compounds of the present invention are specific PAF antagonists which can exist in various isomers. For example, the cyclopentane derivatives of formula (A) can exist in four different stereoisomers as shown in Scheme I. Each stereoisomers in turn exists in a pair of .+-. enantiomers. ##STR2##
These isomers bear a close relationship to the PAF antagonistic activity observed for the compounds within the scope of this invention.
Accordingly, it is the object of the present invention to prepare the most potent isomers of known or novel cyclopentane derivatives as PAF antagonists and use them for the treatment of various diseases including prevention of platelet aggregation, hypotension, inflammation, asthma, lung edema, adult respiratory distress syndrome, various shock syndromes, cardiovascular disorders and other related skeletal-muscular disorders.
Another object of the present invention is to develop processes for the preparation of the 1,3-diarylcyclopentane derivatives.
A further object of the present invention is to provide acceptable pharmaceutical compositions containing one or more of the cyclopentane derivatives as the active ingredient. As PAF antagonists, these novel compositions should be effective in the treatment of various PAF-induced diseases.
Finally, it is the object of this invention to provide a method of treatment comprising the administration of a therapeutically sufficient amount of these PAF antagonists to a patient suffering from various disorders including inflammation, e.g., osteoarthritis, rheumatoid arthritis, gout, and nephritis, hypotension, shock, psoriasis, allergic or skin diseases, asthma, pain especially dental pain, peptic or stomach ulcer, lung edema, adult respiratory distress syndrome or stroke and other cardiovascular disorders.